Conversion Dosing Guide: From epoetin alfa to Aranesp® in patients with anemia due to CKD on dialysis Indication Aranesp® (darbepoetin alfa) is indicated for the treatment of anemia due to chronic kidney disease (CKD), including patients on dialysis and patients not on dialysis. Limitations of Use • Aranesp® has not been shown to improve quality of life, fatigue, or patient well-being. • Aranesp® is not indicated for use as a substitute for red blood cell transfusions in patients who require immediate correction of anemia. Please see Important Safety Information, including Boxed WARNINGS about INCREASED RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, THROMBOSIS OF VASCULAR ACCESS AND TUMOR PROGRESSION OR RECURRENCE, on pages 2 and 3. Important Safety Information including Boxed WARNINGS • Aranesp® is contraindicated in patients with: WARNING: ESAs INCREASE THE RISK OF DEATH, – Uncontrolled hypertension MYOCARDIAL INFARCTION, STROKE, VENOUS – Pure red cell aplasia (PRCA) that begins after treatment with Aranesp® or other THROMBOEMBOLISM, THROMBOSIS OF VASCULAR erythropoietin protein drugs ACCESS AND TUMOR PROGRESSION OR RECURRENCE – Serious allergic reactions to Aranesp® Chronic Kidney Disease: • Use caution in patients with coexistent cardiovascular disease and stroke. • Patients with CKD and an insufficient hemoglobin response to ESA therapy may be • In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and at even greater risk for cardiovascular reactions and mortality than other patients. stroke when administered erythropoiesis-stimulating agents A rate of hemoglobin rise of > 1 g/dL over 2 weeks may contribute to these risks. (ESAs) to target a hemoglobin level of greater than 11 g/dL. • In controlled clinical trials, ESAs increased the risk of death in patients undergoing ® coronary artery bypass graft surgery (CABG) and the risk of deep venous • No trial has identified a hemoglobin target level, Aranesp thrombosis (DVT) in patients undergoing orthopedic procedures. dose, or dosing strategy that does not increase these risks. • Control hypertension prior to initiating and during treatment with Aranesp®. ® • Use the lowest Aranesp dose sufficient to reduce the need • Aranesp® increases the risk of seizures in patients with CKD. Monitor patients for red blood cell (RBC) transfusions. closely for new-onset seizures, premonitory symptoms, or change in seizure frequency. Cancer: • For lack or loss of hemoglobin response to Aranesp®, initiate a search for • ESAs shortened overall survival and/or increased the risk of causative factors. If typical causes of lack or loss of hemoglobin response are tumor progression or recurrence in clinical studies of excluded, evaluate for PRCA. patients with breast, non-small cell lung, head and neck, • Cases of PRCA and of severe anemia, with or without other cytopenias that arise lymphoid, and cervical cancers. following the development of neutralizing antibodies to erythropoietin have been • To decrease these risks, as well as the risk of serious reported in patients treated with Aranesp®. cardiovascular and thromboembolic reactions, use the – This has been reported predominantly in patients with CKD receiving ESAs by lowest dose needed to avoid RBC transfusions. subcutaneous administration. • Use ESAs only for anemia from myelosuppressive – PRCA has also been reported in patients receiving ESAs for anemia related to chemotherapy. hepatitis C treatment (an indication for which Aranesp® is not approved). • ESAs are not indicated for patients receiving – If severe anemia and low reticulocyte count develop during treatment with myelosuppressive chemotherapy when the anticipated Aranesp®, withhold Aranesp® and evaluate patients for neutralizing antibodies outcome is cure. to erythropoietin. ® – Permanently discontinue Aranesp in patients who develop PRCA following • Discontinue following the completion of a chemotherapy ® course. treatment with Aranesp or other erythropoietin protein drugs. Do not switch patients to other ESAs. • Serious allergic reactions, including anaphylactic reactions, angioedema, bronchospasm, skin rash, and urticaria may occur with Aranesp®. Immediately and permanently discontinue Aranesp® if a serious allergic reaction occurs. • Blistering and skin exfoliation reactions including Erythema multiforme and Stevens- Johnson Syndrome (SJS)/Toxic Epidermal Necrolysis (TEN), have been reported in patients treated with ESAs (including Aranesp®) in the postmarketing setting. Discontinue Aranesp® therapy immediately if a severe cutaneous reaction, such as SJS/TEN, is suspected. Please see accompanying Aranesp® full Prescribing Information, • Adverse reactions (≥ 10%) in Aranesp® clinical studies in patients with CKD were including Boxed WARNINGS, and Medication Guide. hypertension, dyspnea, peripheral edema, cough, and procedural hypotension. 2 3 Converting from epoetin alfa to Aranesp® in adult and pediatric patients with CKD on dialysis ® 1 Use the FDA-approved ESA conversion table in the Aranesp PI CONVERSION EXAMPLES FOR ADULT PATIENTS ON DIALYSIS1 ® < 1,500 6.25 * Previous epoetin alfa dose: Aranesp starting dose: 1,500 to 2,499 6.25 6.25 Total weekly epoetin alfa QW Aranesp® 2,500 to 4,999 12.5 10 TIW epoetin alfa × 3 =(TIW 9,000 x 3) Units Conversion dose 5,000 to 10,999 25 20 11,000 to 17,999 40 40 18,000 to 33,999 60 60 3,000 Units/administration × 3 = 9,000 Units/week 25 mcg 34,000 to 89,999 100 100 3,500 Units/administration × 3 = 10,500 Units/week 25 mcg ≥ 90,000 200 200 4,000 Units/administration × 3 = 12,000 Units/week 40 mcg 4,500 Units/administration × 3 = 13,500 Units/week 40 mcg Aranesp® is administered QW or Q2W1 • Administer Aranesp® once weekly in patients who were receiving • The dose conversions depicted above do not accurately estimate the epoetin alfa 2 to 3 times weekly ® once-monthly dose of Aranesp in patients with CKD not on dialysis • Administer Aranesp® once every 2 weeks in patients who were receiving epoetin alfa once weekly *For pediatric patients receiving a weekly epoetin alfa dose of • Maintain the route of administration (intravenous or subcutaneous injection) < 1,500 Units/week, the available data are insufficient to determine an Aranesp® conversion dose. • Pediatric patients with CKD: Aranesp® safety and efficacy were similar ® QW = once weekly; TIW = 3 times weekly; Q2W = once every 2 weeks; between adults and pediatric patients with CKD when Aranesp was PI = prescribing information. used for initial treatment of anemia or patients were transitioned from treatment with epoetin alfa to Aranesp® Please see Important Safety Information, including Boxed WARNINGS, on pages 2 and 3. 4 5 Dosing information: Aranesp® (darbepoetin alfa) for anemia due to CKD in patients on dialysis • In controlled trials, patients experienced greater risks for death, MONITORING serious adverse cardiovascular reactions, and stroke when administered ESAs to target a Hb level of greater than 11 g/dL. Following initiation of therapy and after each dose adjustment, monitor Hb at least weekly until Hb is stable and suffi cient to minimize the need for RBC transfusion. • No trial has identified a Hb target level, Aranesp® dose, or • Thereafter, Hb should be monitored at least monthly, provided that Hb levels dosing strategy that does not increase these risks. remain stable. • Individualize dosing and use the lowest dose of Aranesp® sufficient to reduce the need for RBC transfusions. DOSE ADJUSTMENTS • Physicians and patients should weigh the possible benefits of • When adjusting therapy, consider Hb rate of rise, rate of decline, ESA decreasing transfusions against the increased risks of death and responsiveness, and Hb variability. other serious cardiovascular adverse events. – A single Hb excursion may not require a dosing change. – Do not increase the dose more frequently than once every 4 weeks. Considerations – Decreases in dose can occur more frequently. • Correct or exclude other causes of anemia before initiating Aranesp®. – Avoid frequent dose adjustments. • Evaluate the iron status in all patients before and during treatment. REDUCE OR INTERRUPT DOSE INCREASE DOSE • Administer supplemental iron therapy if serum ferritin is < 100 mcg/L or • If Hb rises rapidly (eg, more than 1 g/dL in any 2-week • If the Hb has not serum transferrin saturation is < 20%. The majority of patients with CKD period), reduce the dose by 25% or more as needed, increased by will require supplemental iron during the course of ESA therapy. to reduce rapid responses. more than 1 g/dL after • Appropriately control hypertension prior to initiation of and during treatment FOR ADULT PATIENTS WITH CKD ON DIALYSIS • reduce or interrupt dose if the Hb level approaches ® 4 weeks of with Aranesp . or exceeds 11 g/dL. therapy, increase – Reduce or withhold Aranesp® if blood pressure becomes difficult to control. FOR PEDIATRIC PATIENTS (LESS THAN 18 YEARS) WITH CKD the dose • If the hemoglobin level approaches or exceeds 12 g/dL, by 25% when reduce or interrupt the dose of Aranesp®. appropriate. INITIATING ARANESP® FOR ADULT PATIENTS WITH CKD ON DIALYSIS Patients who do not respond adequately to Aranesp® • Initiate Aranesp® treatment when the Hb level is < 10 g/dL. • For patients who do not respond adequately over a 12-week escalation • QW recommended starting dose: • Q2W recommended starting dose: period, increasing the Aranesp® dose further is unlikely to improve 0.45 mcg/kg as an IV or SC injection 0.75 mcg/kg as